Hepatitis C virus (HCV) infection is recognized as a worldwide health problem affecting over 170 million individuals. In the United States, over 4 million peoples have been infected and 12,000 deaths yearly are due to hepatitis C. HCV is the most common reason for liver transplantation and accounts for one-third of hepatocellular carcinoma. Prevention of the HCV infection is impeded by the lack of protective vaccines and current therapies against HCV are unsatisfactory. There is clearly an urgent need for the development of new drugs. The molecular mechanisms of viral replication and viral assembly of HCV are poorly understood. It has been shown recently that nucleocapsid-like particles of HCV can be assembled from the HCV core protein that are identical to the HCV nucleocapsid from sera of infected patients. The aim of this proposal is to characterize the HCV core and capsid using macromolecular crystallography and to characterize the packaging signal on the viral RNA. The HCV core protein is the viral subunit of the HCV capsid. It appeared in the last few years that this protein is also very important for the pathogenesis of the disease by inducing cancer, cirrhosis and inflammation of the liver tissue. The resolution of the three-dimensional structure of this protein and the capsid will not only help us to characterize the protein-protein interactions between the proteins subunits, the interaction between the subunits and the nucleic acid but also to resolve the surface of the capsid that interacts with several host factors responsible for different aspects of the pathogenesis of the disease. Altogether, the determination of the structure of the capsid will facilitate the development of research programs that aim to inhibit the assembly of the virus, a novel and very promising target for drug development.